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cADPR Does Not Activate TRPM2

cADPR is a second messenger that releases Ca(2+) from intracellular stores via the ryanodine receptor. Over more than 15 years, it has been controversially discussed whether cADPR also contributes to the activation of the nucleotide-gated cation channel TRPM2. While some groups have observed activat...

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Autores principales: Riekehr, Winnie Maria, Sander, Simon, Pick, Jelena, Tidow, Henning, Bauche, Andreas, Guse, Andreas H., Fliegert, Ralf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8949931/
https://www.ncbi.nlm.nih.gov/pubmed/35328585
http://dx.doi.org/10.3390/ijms23063163
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author Riekehr, Winnie Maria
Sander, Simon
Pick, Jelena
Tidow, Henning
Bauche, Andreas
Guse, Andreas H.
Fliegert, Ralf
author_facet Riekehr, Winnie Maria
Sander, Simon
Pick, Jelena
Tidow, Henning
Bauche, Andreas
Guse, Andreas H.
Fliegert, Ralf
author_sort Riekehr, Winnie Maria
collection PubMed
description cADPR is a second messenger that releases Ca(2+) from intracellular stores via the ryanodine receptor. Over more than 15 years, it has been controversially discussed whether cADPR also contributes to the activation of the nucleotide-gated cation channel TRPM2. While some groups have observed activation of TRPM2 by cADPR alone or in synergy with ADPR, sometimes only at 37 °C, others have argued that this is due to the contamination of cADPR by ADPR. The identification of a novel nucleotide-binding site in the N-terminus of TRPM2 that binds ADPR in a horseshoe-like conformation resembling cADPR as well as the cADPR antagonist 8-Br-cADPR, and another report that demonstrates activation of TRPM2 by binding of cADPR to the NUDT9H domain raised the question again and led us to revisit the topic. Here we show that (i) the N-terminal MHR1/2 domain and the C-terminal NUDT9H domain are required for activation of human TRPM2 by ADPR and 2′-deoxy-ADPR (2dADPR), (ii) that pure cADPR does not activate TRPM2 under a variety of conditions that have previously been shown to result in channel activation, (iii) the cADPR antagonist 8-Br-cADPR also inhibits activation of TRPM2 by ADPR, and (iv) cADPR does not bind to the MHR1/2 domain of TRPM2 while ADPR does.
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spelling pubmed-89499312022-03-26 cADPR Does Not Activate TRPM2 Riekehr, Winnie Maria Sander, Simon Pick, Jelena Tidow, Henning Bauche, Andreas Guse, Andreas H. Fliegert, Ralf Int J Mol Sci Article cADPR is a second messenger that releases Ca(2+) from intracellular stores via the ryanodine receptor. Over more than 15 years, it has been controversially discussed whether cADPR also contributes to the activation of the nucleotide-gated cation channel TRPM2. While some groups have observed activation of TRPM2 by cADPR alone or in synergy with ADPR, sometimes only at 37 °C, others have argued that this is due to the contamination of cADPR by ADPR. The identification of a novel nucleotide-binding site in the N-terminus of TRPM2 that binds ADPR in a horseshoe-like conformation resembling cADPR as well as the cADPR antagonist 8-Br-cADPR, and another report that demonstrates activation of TRPM2 by binding of cADPR to the NUDT9H domain raised the question again and led us to revisit the topic. Here we show that (i) the N-terminal MHR1/2 domain and the C-terminal NUDT9H domain are required for activation of human TRPM2 by ADPR and 2′-deoxy-ADPR (2dADPR), (ii) that pure cADPR does not activate TRPM2 under a variety of conditions that have previously been shown to result in channel activation, (iii) the cADPR antagonist 8-Br-cADPR also inhibits activation of TRPM2 by ADPR, and (iv) cADPR does not bind to the MHR1/2 domain of TRPM2 while ADPR does. MDPI 2022-03-15 /pmc/articles/PMC8949931/ /pubmed/35328585 http://dx.doi.org/10.3390/ijms23063163 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Riekehr, Winnie Maria
Sander, Simon
Pick, Jelena
Tidow, Henning
Bauche, Andreas
Guse, Andreas H.
Fliegert, Ralf
cADPR Does Not Activate TRPM2
title cADPR Does Not Activate TRPM2
title_full cADPR Does Not Activate TRPM2
title_fullStr cADPR Does Not Activate TRPM2
title_full_unstemmed cADPR Does Not Activate TRPM2
title_short cADPR Does Not Activate TRPM2
title_sort cadpr does not activate trpm2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8949931/
https://www.ncbi.nlm.nih.gov/pubmed/35328585
http://dx.doi.org/10.3390/ijms23063163
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